After asphyxial, traumatic, toxic, infectious, degenerative, metabolic, ischemic or hypoxic insults to the central nervous system (CNS) of man a certain degree of neural damage may result. For example, such neural damage can occur in cases of perinatal asphyxia associated with intrapartum fetal distress such as following abruption, cord occlusion or associated with intrauterine growth retardation; perinatal asphyxia associated with failure of adequate resuscitation or apnea; severe neural insults associated with near miss drowning, carbon monoxide inhalation, ammonia of other gaseous intoxication, cardiac arrest, collapse, coma, meningitis, hypoglycemia, or status epilepticus; episodes of cerebral asphyxia associated with coronary bypass surgery; cerebral anoxia or ischemia associated with stroke, hypotensive episodes, hypertensive crises; cerebral trauma; or cerebral degenerative diseases such as Alzheimers disease and multiple sclerosis.
Such neural damage can involve several different cell types of the CNS. For example, periventricular leucomalacia, a lesion which affects the periventricular oligodendrocytes is generally considered to be a consequence of hypoxicischemic injury to the developing preterm brain. Bejar, et al., Am. J. Obstet. Gynecol., 159:357-363 (1988); Sinha, et al., Arch. Dis. Child., 65:1017-1020 (1990); Young, et al., Ann. Neurol., 12:445-448 (1982). Further cholinergic neuronal cell bodies are absent from most regions of the cortex in primates (Mesulam, et al., Neurosci., 12:669-686 (1984)) and rats (Brownstein, et al., in Handbook of Chemical Neuroanatomy, Classical Transmitters in the CNS, pp. 23-53 (Elsevier, 1984)). Damage to the cerebral cortex by trauma, asphyxia, ischemia, toxins or infection is frequent and may cause sensory, motor or cognitive deficits. Glial cells which are non-neuronal cells in the CNS are necessary for normal CNS function. Infarcts are a principle component of hypoxic-ischemia induced injury and loss of glial cells is an essential component of infarction. Multiple sclerosis is associated with loss of myelin and oligodendrocytes, similarly Parkinson's disease is associated with loss of dopaminergic neurons.
Several growth factors have been reported to be induced after transient hypoxic-ischemia in the brain. After postasphyxial seizures, the proto-oncogene c-fos is induced in surviving neurons and in glial cells from infarcted regions. Gunn, et al., Brain Res., S31:105-116 (1991). Nerve growth factor (NGF) synthesis is increased after hypoxia or seizures in the hippocampus and cerebral cortex. Lorez, et al., Neurosci. Lett., 98:339-344 (1989); Gall, et al., Science, 245:758-761 (1989). However, little is known of the role of cytokines in brain injury. Glial cells have been shown to produce a number of cytyokines including interleukin 3 (lL-3) and interleukin 6 (lL-6). Interleukin 1 (lL-1) has been reported to be elevated in cerebrospinal fluid after head injury in humans. McClain, et al., J. Lab. Clin. Med., 110:48-54 (1987).
Transforming growth factor beta (TGF-.beta.) is another example of a cytokine and is a multifunctional polypeptide implicated in the regulation of cellular or tissue response to injury or stress. For a general review of TGF-.beta. and its actions, see Sporn, et al., Science, 233:532-534 (1986); Sporn et al., J. Cell Biol., 105:1039-1045 (1987); Sporn, et al., Nature, 3232:217-219 (1988); and Sporn, et al, in Peptide Growth Factors and Their Receptors l, pp.419-472 (Springer-Verlag, 1990). TGF-.beta. is found in various mammalian tissues, such as bone, platelets, and placenta, and methods for purifying the polypeptide from such natural sources, as well as for producing it in recombinant cell culture, have been described. See, for example, Assoian, et al., J. Biol. Chem., 258:7155-7160 (1983); Frolik, et al., Proc. Nat. Acad. Sci., 80:3676-3680 (1983); Heimark, et al., Science, 233:1078-1080 (1986); Sporn, et al., U.S. Pat. No. 5,104,977; Derynck, et al., Nature, 316:701-705 (1985); Derynck, et al., U.S. Pat. No. 4,886,747.
There are several molecular forms of TGF-.beta., including those forms which are commonly referred to as TGF-.beta.1 (Derynck, et al., Nature, 316:701-705 (1985)), TGF-.beta.2 (deMartin, et al., EMBO J., 3673-3677 (1987); Madison, et al., DNA, 7:1-8 (1988)), TGF-.beta.3 (Jakowlew, et al., Mol. Endocrin., 2:747-755 (1988); Ten Dijke, et al., Proc. Nat. Acad. Sci., 85:4715-4719 (1988); Derynck, et al., EMBO J., 7:3737-3743 (1988)), TGF-.beta.4 (Jakowlew, et al., Mol. Endocrin., 2:1186-1195 (1988), and TGF-.beta.5 (Kondaiah, et al., J. Biol. Chem., 265:1089-1093 (1990).
It is an object of the invention to provide methods and pharmaceutical compositions for treating or preventing CNS injury or damage. The invention is based upon the inventors' successful research into the role and effects of TGF-.beta. in the CNS.